Lack of the p50 subunit of nuclear factor-κB increases the vulnerability of hippocampal neurons to excitotoxic injury

Nuclear factor-kappa B (NF-kappa B) is activated in brain cells after various insults, including cerebral ischemia and epileptic seizures. Although cell culture studies have suggested that the activation of NF-kappa B can prevent neuronal apoptosis, the role of this transcription factor in neuronal injury in vivo is unclear, and the specific kappa B subunits involved are unknown. We now report that mice lacking the p50 subunit of NF-kappa B exhibit increased damage to hippocampal pyramidal neurons after administration of the excitotoxin kainate. Gel-shift analyses showed that p50 is required for the majority of kappa B DNA-binding activity in hippocampus. Intraventricular administration of kappa B decoy DNA before kainate administration in wild-type mice resulted in an enhancement of damage to hippocampal pyramidal neurons, indicating that reduced NF-kappa B activity was sufficient to account for the enhanced excitotoxic neuronal injury in p50(-/-) mice. Cultured hippocampal neurons from p50(-/-) mice exhibited enhanced elevations of intracellular calcium levels and increased levels of oxidative stress after exposure to glutamate and were more vulnerable to excitotoxicity than were neurons from p50(+/+) and p50(+/-) mice. Collectively, our data demonstrate an important role for the p50 subunit of NF-kappa B in protecting neurons against excitotoxic cell death.